PMID- 27181203 OWN - NLM STAT- MEDLINE DCOM- 20170901 LR - 20190610 IS - 1476-5594 (Electronic) IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 36 IP - 1 DP - 2017 Jan 5 TI - p27T187A knockin identifies Skp2/Cks1 pocket inhibitors for advanced prostate cancer. PG - 60-70 LID - 10.1038/onc.2016.175 [doi] AB - SCF(Skp2/Cks1) ubiquitinates Thr187-phosphorylated p27 for degradation. Overexpression of Skp2 coupled with underexpression of p27 are frequent characteristics of cancer cells. When the role of SCF(Skp2/Cks1)-mediated p27 ubiquitination in cancer was specifically tested by p27 Thr187-to-Ala knockin (p27T187A KI), it was found dispensable for Kras(G12D)-induced lung tumorigenesis but essential for Rb1-deficient pituitary tumorigenesis. Here we identify pRb and p53 doubly deficient (DKO) prostate tumorigenesis as a context in which p27 ubiquitination by SCF(Skp2/Cks1) is required for p27 downregulation. p27 protein accumulated in prostate when p27T187A KI mice underwent DKO prostate tumorigenesis. p27T187A KI or Skp2 knockdown (KD) induced similar degrees of p27 protein accumulation in DKO prostate cells, and Skp2 KD did not further increase p27 protein in DKO prostate cells that contained p27T187A KI (AADKO prostate cells). p27T187A KI activated an E2F1-p73-apoptosis axis in DKO prostate tumorigenesis, slowed disease progression and significantly extended survival. Querying co-occurrence relationships among RB1, TP53, PTEN, NKX3-1 and MYC in TCGA of prostate cancer identified co-inactivation of RB1 and TP53 as the only statistically significant co-occurrences in metastatic castration-resistant prostate cancer (mCRPC). Together, our study identifies Skp2/Cks1 pocket inhibitors as potential therapeutics for mCRPC. Procedures for establishing mCRPC organoid cultures from contemporary patients were recently established. An Skp2/Cks1 pocket inhibitor preferentially collapsed DKO prostate tumor organoids over AADKO organoids, which spontaneously disintegrated over time when DKO prostate tumor organoids grew larger, setting the stage to translate mouse model findings to precision medicine in the clinic on the organoid platform. FAU - Zhao, H AU - Zhao H AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Lu, Z AU - Lu Z AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Bauzon, F AU - Bauzon F AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Fu, H AU - Fu H AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Cui, J AU - Cui J AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Locker, J AU - Locker J AD - Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. FAU - Zhu, L AU - Zhu L AD - Departments of Developmental and Molecular Biology, and Ophthalmology and Visual Sciences, and Medicine, The Albert Einstein Comprehensive Cancer Center and Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA. LA - eng GR - P30 DK041296/DK/NIDDK NIH HHS/United States GR - R01 DK061153/DK/NIDDK NIH HHS/United States GR - R01 CA127901/CA/NCI NIH HHS/United States GR - R01 CA131421/CA/NCI NIH HHS/United States GR - R01 CA201458/CA/NCI NIH HHS/United States GR - P30 CA013330/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160516 PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (CKS1B protein, human) RN - 0 (E2F1 Transcription Factor) RN - 0 (Retinoblastoma Protein) RN - 0 (S-Phase Kinase-Associated Proteins) RN - 0 (Tumor Protein p73) RN - 0 (Tumor Suppressor Protein p53) RN - 147604-94-2 (Cyclin-Dependent Kinase Inhibitor p27) RN - EC 2.7.11.22 (CDC2-CDC28 Kinases) SB - IM MH - Animals MH - Apoptosis/genetics MH - CDC2-CDC28 Kinases/*metabolism MH - Cell Line, Tumor MH - Cell Transformation, Neoplastic/genetics/metabolism MH - Cyclin-Dependent Kinase Inhibitor p27/*genetics/metabolism MH - Disease Progression MH - E2F1 Transcription Factor/metabolism MH - Gene Knock-In Techniques MH - Humans MH - Male MH - Mice MH - Mice, Knockout MH - Mice, Transgenic MH - Neoplasm Staging MH - Prostate/metabolism MH - Prostatic Neoplasms/drug therapy/*genetics/*metabolism/pathology MH - Retinoblastoma Protein/deficiency MH - S-Phase Kinase-Associated Proteins/*metabolism MH - Tumor Protein p73/genetics/metabolism MH - Tumor Suppressor Protein p53/deficiency MH - Ubiquitination PMC - PMC5112153 MID - NIHMS780459 COIS- The authors declare no conflict of interest. EDAT- 2016/05/18 06:00 MHDA- 2017/09/02 06:00 PMCR- 2017/07/05 CRDT- 2016/05/17 06:00 PHST- 2016/01/06 00:00 [received] PHST- 2016/03/04 00:00 [revised] PHST- 2016/04/11 00:00 [accepted] PHST- 2016/05/18 06:00 [pubmed] PHST- 2017/09/02 06:00 [medline] PHST- 2016/05/17 06:00 [entrez] PHST- 2017/07/05 00:00 [pmc-release] AID - onc2016175 [pii] AID - 10.1038/onc.2016.175 [doi] PST - ppublish SO - Oncogene. 2017 Jan 5;36(1):60-70. doi: 10.1038/onc.2016.175. Epub 2016 May 16.